Every 4-6 months during our oncology training, we rotate onto a new tumour site.
As a diligent trainee before starting a new rotation, I like to read up on the guidelines and make sure I know what I'm talking about.
However, with all the fantastic advances constantly being made in the field of cancer medicine, sometimes this can be a bit of a challenge.
Never more so than when I started on my renal cancer job!
So today I thought I would talk about my experience with metastatic renal cancer, the treatments available, and the journey to learn about them. Welcome to a day in the life of a medical oncology registrar on renal cancer.
Powering up the skills
One of the skills you learn as a medical student and as a trainee is where to source your information.
These evolve as you change jobs, but for most oncology jobs I've done, I look to the local treatment guidelines and the European Society for Medical Oncology (ESMO) guidelines and get myself up to speed.
So fast forward to my first clinics, and I'm discussing our patients with the consultants before seeing them. During one of these discussions, I was quizzed on why I was suggesting a particular line of treatment at which point I was told "Oh, no. Sorry Sam - the guidance from ESMO is out of date. There are 8 first lines of treatment now..." Greeeaaaatttt...
And so the story of the 8 first-line treatment options begins.
So let's backtrack - to the resources!
The difficult problem of too many resources
It can be difficult to know where to get information from these days. We are all overwhelmed constantly with it. (I realise the immediate irony of this whilst writing a blog post)
Working in the field of medicine this is no different. If anything, the overwhelming number of professional medical resources is the epitome of the problem. It is estimated that medical knowledge doubles every 73 days, which is just mind-boggling and bonkers. No one can keep up with that.
With this plethora of information comes a whole set of new problems, such as inconsistency, contradiction, out-of-date resources, and regional differences of practice... to name but a few. This is indeed why a career in medicine is quoted as being 'A commitment to lifelong learning'. For those potential medical students out there, It really, really is, and you've got to run to keep up because things change fast.
So let's dig into the resources available to try and work out the right approach to skilling up on the medical knowledge front.
Books
Books are great, they look pretty on a shelf.
I love a nice collection of books, and within the text, they usually provide a narrative, even within medical texts.
(I especially love the mini-stories and quips in the Oxford Handbook of Medicine). But, books are out of date by the time they are printed. So unless you're reading about long-established fundamentals of physiology or the ilk, they are of no use, especially in Oncology.
Local guidelines
Local guidelines should be up to date - but they are often brief snapshots or flowcharts without any explanation. Maybe a reference here or there. They also rely on someone writing them, and then these new guidelines need to be agreed upon by whoever it is, and then signed off and published onto your local intranet or whatever.
It all takes time.
And as soon as a new treatment is available, this process needs to start again. Not ideal. And in this case, not updated :)
The Internet
Not really narrowing it down here. You've got to know where to look.
Every guideline ever written will be on there, still.
There are searchable data summaries that people may recommend, resources such as 'UpToDate' - which is fantastic - but that particular resource costs a shedload, and the hospitals (at least the last two I've worked at) can't afford the user licenses.
It's gotta be practical and affordable. So, you see the problem.
Specific Internets
For cancer medicine, there are some tumour-specific guidelines. In this case, the EAU was the winner for my needs. The EAU represents the leading authority within Europe on urological practice, research, and education - worth checking out: https://uroweb.org/
So begins the analysis...
The 8 first-line treatment options for metastatic renal cancer
Starting at the endpoint, we can build up a picture around them.
Here are all the therapy combinations we might give:
Immune checkpoint inhibitor and TKI combinations :
Ipilimumab + Nivolumab
Cabozantinib + Nivolumab
Axitinib + Avelumab
Axitinib + Pembrolizumab
Lenvatinib + Pembroluzimab
TKI single agents:
Sunitinib
Pazopanib
Axitinib
Cabozantinib
Lenvatinib
That's a lot of choices of drugs. Study hats on.
In case you're wondering how to differentiate the endlessly unpronounceable names :D Anything ending in 'mabs' means Monoclonal Antibodies Anything ending in 'nibs' means Small-molecule inhibitor (“nib” is verbal shorthand for “inhibit”) of kinase enzymes. More specifically in this context: “Tinib” is used for tyrosine kinase inhibitors.
Wait I hear you say?! I thought you were talking about checkpoint inhibitors and now you're saying these are monoclonal antiwhatties?!
Well done for your keen eye ;) Not all immunotherapy is made from monoclonal antibodies
While monoclonal antibodies (MABs) are a significant subset of immunotherapy, there are other types as well. For a segue into the difference between checkpoint inhibitors and monoclonal antibodies see the end of the post.
So how do we decide what to choose?!
So that is the big question here, and there are a number of facets to answering it. But most of those answers are going to come from trials.
Trials trials trials
As you plod your way through medical training you start to realise that it's all about the trials. Evidence-based medicine is a key phrase for a reason. It should drive and direct everything we do, otherwise, we're just making up stuff in an authoritative way whilst wearing a fancy stethoscope. Hands up if you're guilty of that. However.
It's easy, especially as a medical student and in your early years as a junior doctor, to take trials at face value.
Because you don't really know any better at that stage. If some trial says this treatment has a positive effect on the patient's condition, then it makes sense that this is the one we should be using.
However, I think it takes a lot of time and experience to have the skills to be able to constructively and appropriately pull the trial data apart.
There is a skill and a learning process in appreciating that trials aren't perfect, and that they may not be representative of the patient and person in front of you.
Things aren't black and white in trials, nothing in medicine is.
So the question you should be asking is:
Is this treatment going to help my patient?
There is no perfect trial to answer this question. I mean, unless we clone our patient, blindly give one of the clones a placebo and the other the actual treatment, keep them both in the same conditions between the 3 monthly scans, and see if one gets better. In fact, we'd probably need hundreds of clones to make the study powered correctly for an answer.
So then you've cloned your patient and their tumour hundreds of times, hoping that the treatment works and doesn't have too many side effects. But by then you'll have hundreds of clones - all with a tumour you've inflicted upon them - with only half being treated with an actual treatment and the rest on a placebo.
It's all starting to feel a bit unethical.
So let's not go down this road of cloning our patients and fall back on the second best thing, a trial not involving clones.
Tearing apart the trials
The whole idea of tearing apart the trials was a bit of a lightbulb moment for me.
I was discussing a patient with a consultant, and I thought I was being clever, pulling out the trial data for the patient in question, quoting hazard ratios and all.
Until she pointed out that of the 1000 patients this trial was done on, only about 5% matched the situation the patient was in. Ouch.
The words "Do you think this trial will be representative of the patient in front of you?" will be etched on my mind forever.
I'll never take a trial at face value again without drilling into the data, and neither should you.
So which Trials and what were the outcomes?!
Let's have a look and summary of the trials involved, starting with the combination treatments:
Ipilimumab + Nivolumab -> Checkmate 214
(Nivo plus Ipi vs Sunitinib)
Cabozantinib + Nivolumab -> CheckMate 9ER
(Nivo plus Cabo vs Sunitinib)
Axitinib + Avelumab -> JAVELIN Renal 101
(Axi plus Ave vs Sunitinib)
Axitinib + Pembrolizumab -> KEYNOTE-426
(Axi plus Pembro vs Sunitinib)
Lenvatinib + Pembroluzimab -> CLEAR
(Lenv plus Pembro vs Sunitinib)
So immediately I can see the first fly in the ointment.
All of these trial outcomes have been compared to Sunitinib.
Why?
Sunitinib was the standard first-line treatment for about 10 years before new treatments came onto the scene. Gotchya.
So what's the problem?
The problem is that none of these treatments have been compared against each other.
So when we are trying to choose between them and explain comparative efficacy to a patient, it makes this a bit tricky.
Especially when they ask the inevitable question, of which treatment is best?
We have to infer, without clear evidence, the benefit of one treatment over the other.
Hmm. Plot thickens.
So let's have a look at the first couple of trials
Trial No.1
Ipilimumab + Nivolumab -> Checkmate 214
I love the names they give these things. They sound so imposing.
The CheckMate 214 trial is a Phase 3, randomized, open-label study that evaluated the combination of nivolumab plus ipilimumab versus sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC).
To keep things simple(er) I'm going to just talk about overall survival and not discuss the co-primary endpoints (objective response rate and progression-free survival)
The conclusion of this trial states that overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients.
So digging into that a bit, in patients who have never had any treatment for their renal cancer before you can see the 18-month overall survival rate was 75% with nivolumab plus ipilimumab and 60% with sunitinib.
Sounds great right? You'd think it's a no-brainer. But...
Check out the exclusion criteria:
None of the patients had brain metastases or autoimmune disease, and they weren't on steroids or using immunosuppressants.
Hmm. Okay. More information to add to the pie. It makes sense that we should be careful in giving immunotherapy to patients with autoimmune conditions because they can make things worse, so that is more to consider.
That's where taking a patient's past medical history accurately comes into play :D
Speaking of side effects:
It's also worth noting that the side effects were bad enough to stop treatment in 22% of the immunotherapy group vs 12% in the Sunitinib group.
And then, back to the key message.
How well does the trial data reflect the person in front of you? Let's consider a few points...
Pathology:
All of the patients in the trial had clear cell renal cancer, not papillary or something else, what does your patient have? If it's not clear cell - we can't apply the findings here. Risk category:
The benefit quoted was shown in intermediate and poor-risk patients, if your patient is favourable risk you need to dig deeper into the data and see what the outcomes for that subset are.
Equivalent disease:
In the data breakdown, how many patients had the same number and sites of metastasis as your patient does? Is this trial representative of their cancer? The most common sites of metastasis in this trial were lung and lymph nodes, with a smaller proportion of bone and liver metastasis.
Summary
Okay, a lot to think about and process on that trial. Immunotherapy comes with a benefit to overall survival for patients in intermediate and poor-risk, but the side effects can be challenging and you've got to be careful of any underlying autoimmune conditions.
On board!? Great :D Next.
Trial No.2
Cabozantinib + Nivolumab -> CheckMate 9ER -> (Nivo plus Cabo vs Sunitinib)
The CheckMate 9ER trial was very similar to the previous one, in that it was a randomized, open-label trial, for previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab plus cabozantinib or sunitinib.
Let the games begin.
The conclusion states that Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response
So let's have a deeper dive into that data.
The results state that the probability of overall survival at 12 months 85.7% with nivolumab plus cabozantinib and 75.6% with sunitinib.
Well, that's brilliant, but wait! - The previous conclusion stated the results at 18 months.
So we need to look at the data and try and work out where the overall survival is on the Kaplan Meier charts on the trials to try and find the equivalent overall survival points.
So looking back at the charts, 18-month overall survival rate in this trial was 77.4% with nivolumab plus cabozantinib and 72.9% with sunitinib.
Woah, waity here - I suddenly realise the overall survival between the two sunitinib groups is different - 60% vs 72.% ... what the heck is going on here?!
So then you do a bit of a deep dive on that and get the following answers :
The overall survival of patients on sunitinib in the CheckMate 9ER and CheckMate 214 trials was different because of several factors, such as:
Patient population: The CheckMate 9ER trial included patients with any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk category, whereas the CheckMate 214 trial enrolled only intermediate- or poor-risk patients. The favorable-risk patients in the CheckMate 9ER trial had longer overall survival than the intermediate- or poor-risk patients in both trials.
Treatment duration: The median duration of treatment with sunitinib was longer in the CheckMate 9ER trial (9.2 months) than in the CheckMate 214 trial (7.8 months), which could reflect better tolerability or efficacy of sunitinib in the CheckMate 9ER trial.
Subsequent therapy: The proportion of patients who received subsequent therapy after discontinuing sunitinib was higher in the CheckMate 9ER trial (54%) than in the CheckMate 214 trial (39%), which could have an impact on the overall survival outcomes.
I mean, I'm not saying we are comparing apples and oranges here but... jeezo!
Clearly the the overall survival of patients on sunitinib in the CheckMate 9ER and CheckMate 214 trials are not directly comparable and should be interpreted with caution.
Let's pause the analysis there at the risk of turning this blog post into a systematic review :D
Fast forward to the clinic
So you're the doctor - you've worked hard and done your homework, and you've got pockets of data from all the different trials floating around in your mind - none of which are directly comparable, but they give you a picture of a pathway of treatment.
(Providing your health authority has approved all the treatments in the respective setting- that's a story for another time)
It's clinic day - you've read all about your patient and got a plan of what you think would work, at the back of your mind you've got a plan for second-line and third-line treatments should the patient not tolerate the treatment or there is progression of the disease.
Rock and roll. You're ready (times the 3 new patients you're going to see today.)
Now let's imagine you're the patient
You've got a doctor in front of you and you've come to your first oncology appointment and they start talking to you about your diagnosis and potential treatments.
You're understandably frightened and are probably going to leave the room not remembering your own name, let alone the doctor you met or anything they said.
What did he say about treatment again... ?
It's probably a good time to segue into the realm of informed consent.
Informed Consent
Informed consent is a principle in medical ethics and medical law that a patient must have sufficient information and understanding before making decisions about their medical care.
This type of communication lets the patient ask questions and accept or deny treatment
Informed consent means that the patient must be given all of the information about what the treatment involves, including the benefits and risks, whether there are reasonable alternative treatments, and what will happen if treatment does not go ahead.
Informed consent is not a simple yes/no answer in many situations, but a process of dialogue and mutual respect between the patient and the healthcare provider
So that all makes sense... but I'm sure now you see the challenge...
How do you convey even the tip of the iceberg of this huge volume of data and information to a patient in a stressful and time-constrained situation?
I've been studying medicine for over a decade and this stuff can be hard - how can you expect someone from a non-medical background to make an informed treatment decision?
Therein lies the skill, challenge, and the art of being a good oncology doctor I suppose.
Conclusion
I read a wonderful book by Siddhartha Mukherjee called "The Emporor of All Maladies : A Biography of Cancer." He discusses the challenges and dilemmas of communicating with cancer patients, and how different doctors have different styles and approaches. I'll finish on a high with his excerpt:
"Some oncologists thrive on giving information, even when they know that the information might be crushing; others prefer to give information more judiciously, offering details only when they are pressed, or when the situation becomes desperate. Some patients want every morsel of information, no matter how disheartening; others prefer to know as little as possible, or to leave the decision-making entirely in the hands of their physicians. The balance between too much and too little information is delicate and precarious."
So back to the clinic.
If I were a patient sitting in a clinic with renal cancer, I would say, which drug combination will make me live longest?
It's a reasonable question - you'd want to be able to ask that question to your oncologist and get a straight answer.
But, as the doctor, I would say, "Honestly, I don't know."...
"But there are some very good treatment options available that I would recommend, so let's talk about them and we can come up with a plan together".
*** Legal Disclaimer ***
By the way, anything in this blog post obviously doesn't constitute medical advice.
It's a blog post. Do not get your medical advice from blog posts. And that is medical advice. But not officially. Because you got it from my blog post.
So do take that advice, but don't take any more medical advice from blog posts!
Monoclonal Antibodies (MABs) & Checkpoint Inhibitors:
Checkpoint Inhibitors:
Definition: Checkpoint inhibitors are a type of immunotherapy that block different checkpoint proteins.
Target: They specifically target proteins that stop the immune system from attacking cancer cells.
Mechanism: These drugs prevent cancer cells from using checkpoint proteins to suppress the immune response. By doing so, they allow the immune system’s T cells to recognize and attack cancer cells.
Monoclonal Antibodies (MABs):
Definition: Monoclonal antibodies are laboratory-produced antibodies designed to recognize and target specific proteins on the surface of cancer cells.
Immunotherapy Aspect: Some MABs also have an effect on the immune system, making them a type of immunotherapy.
Mechanism: MABs directly bind to specific proteins on cancer cells, interfering with their function or signaling pathways.
Clinical Use: MABs are employed in various cancer treatments, often as targeted therapies.
In summary, checkpoint inhibitors focus on immune system regulation by blocking checkpoint proteins, while monoclonal antibodies directly target specific proteins on cancer cells.
This is definitely a topic for deep-dive understanding and something I will no doubt write about later :)
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